It is well established that there exists a correlation between drug use and the incidence of HIV-1 infection. However, much of what we know about the effects of certain psychoactive drugs, such as heroin or morphine, comes from epidemiological studies which utilize unreliable study populations. Recently, our preliminary data has demonstrated that morphine increases viral burden in the mouse brain. It is the goal of this proposal to extend our knowledge by examining the effects of morphine on HIV-1 infection by utilizing the EcoHIV mouse model. This model employs a chimeric HIV-1 carrying an ecotropic MLV envelope which is capable of infecting mouse cells, and therefore allows for the "natural" infection of mice. Our hypothesis is that morphine will augment the infection of EcoHIV as well as increase the inflammatory effects of the virus in the brain. Aim 1 proposes to investigate whether morphine administration facilitates HIV-1 replication in the brain and synergizes with virus in the induction of neuroinflammation following intracranial virus inoculation. In Specific Aim 2, research is proposed to examine a mechanism by which morphine increases viral burden in the CNS, with a focus on a role for NK cells. Finally in Aim 3, studies are proposed that will investigate the effects of morphine on viral transit to the CNS following intravenous exposure to virus, while focusing on the role of the blood brain barrier to this process. To monitor the severity of infection viral burden will be assessed by measuring levels of gag from several tissues. Immune status will also be monitored given the decrements that morphine exerts on the functioning of the immune system. In addition, the cellular localization of the virus will also be analyzed by utilizing a variant of the EcoHIV virus that expresses GFP. It is the goal of this research to provide an understanding of how morphine effects HIV-1 infection in an immune competent host. Little is known at present about HIV-1 infection in the context of morphine administration in vivo, and utilizing the novel EcoHIV model will allow for the exploration of many of these questions with the ultimate goal of reducing the deleterious effects of combined drug use and HIV infection. PUBLIC HEALTH RELEVANCE: There is clear evidence that both drug abuse and HIV-1 infection are pertinent public health issues. This research proposal aims to investigate these issues by utilizing a mouse model of HIV-1 infection, which allows investigators to examine the effects of both of these health issues in a very reliable laboratory model, with the ultimate goal of discovering means by which to alleviate these health issues.